The serotonin receptors, also known as 5-hydroxytryptamine (5-HT) receptors, are a group of G protein-coupled receptors (GPCRs) and ligand-gated ion channels (LGICs) found in the central and peripheral nervous systems. They are activated by the neurotransmitter serotonin, a natural ligand. Once activated, the serotonin receptors modulate the release of many neurotransmitters, including glutamate, GABA, dopamine, epinephrine/norepinephrine, and acetylcholine; as well as many hormones, including oxytocin, prolactin, vasopressin, cortisol, corticotropin, and substance P. As a result, the serotonin receptors are involved in and influence many different biological and neurological processes such as aggression, anxiety, appetite, cognition, learning, memory, mood, nausea, sleep and thermoregulation. 5-HT receptors are, therefore, targets for a variety of pharmaceutical drugs, including many antidepressants, antipsychotics, anorectics, antiemetics, gastroprokinetic agents and antimigraine agents.
There are seven known serotonin receptor families, which are generally identified by the nomenclature 5HT1 (or 5-HT1) to 5HT7 (5-HT7), and some of these families include a plurality of subtypes. For example, the known subtypes of the 5HT1 family are named from 5HT1a (or 5-HT1a) to 5HT1f (5-HT1f).
5HT1a antagonists have been shown to exhibit cognitive enhancing effects in a number of animal models of learning and memory. They may also have utility in the treatment of anxiety, for enhancing the antidepressant effects of SSRI fluoxetine, and for potentially reversing the sexual dysfunction induced by chronic fluoxetine treatment (see e.g. Childers W. E. et al., (2010) “The synthesis and biological evaluation of quinolyl-piperazinyl piperidines as potent serotonin 5-HT1A antagonists”, J. Med. Chem., 53(10): 4066-4084; and Caliendo G. et al., (2005) “Derivatives as 5HT1A receptor ligands—past and present”, Curr. Med. Chem. 12(15): 1721-1753).
Accordingly, it would be desirable to have further 5HT1a receptor antagonist and inverse agonist compounds; for example, that may be useful as therapeutics or as lead molecules in the treatment of neurological disorders.
5HT1a agonists such as the azapirones (buspirone, gepirone and tandospirone) have been reported to exert anxiolytic and anti-depressive activity in double-blind, placebo-controlled, and comparative trials and as such 5HT1a agonists may also be useful as therapeutics or as lead molecules in the treatment of neurological disorders.
Dopamine receptors are activated by the natural neurotransmitter ligand, dopamine. Like serotonin receptors, a large number of dopamine receptor subtypes are known in humans and other animals. The D4 receptor is generally considered to be dopamine D2-like, in that the activated receptor inhibits the adenylate cyclase enzyme, thereby reducing the intracellular concentration of the second messenger cyclic AMP (cAMP).
The dopamine D4 receptor has been linked to many neurological and psychiatric conditions including schizophrenia, Parkinson's disease, bipolar disorder, addictive behaviours, and eating disorders such as anorexia nervosa, bulimia nervosa and binge eating. In addition, dopamine D4 receptor antagonists have been reported to prevent stress-induced cognition dysfunction in primates (Arnsten et al. (2000), “The selective dopamine D4 receptor antagonist, PNU-101387G, prevents stress-induced cognitive deficits in monkeys”, Neuropsychopharmacology 23, pp 405-410). Consequently, D4 antagonists have been linked to the treatment of cognitive dysfunction and amyotrophic lateral sclerosis. In addition, the dopamine D4 receptor is a target for drugs that are intended to treat schizophrenia and Parkinson's disease. A review of dopamine D4 ligands can be found in Löber S. et al., (2011) “Recent advances in the search for D(3)- and D(4)-selective drugs: probes, models and candidate”, Trends Pharmacol. Sci., 32(3), pp 148-57. For example, a dopamine receptor antagonist L-745,870 has been shown to suppress microglia activation in spinal cord and mitigates the progression in ALS model mice (Tanaka K. et al., (2008) Exp. Neurol., 211(2), pp 378-86). Accordingly, there is a need for further dopamine D4 receptor antagonists for use in treating one or more neurological diseases.
Furthermore, polypharmaceutical drugs (i.e. drugs that show selectivity and activity against more than one useful therapeutic target at the same time), are desirable because of the great potential they offer as new or enhanced therapeutic molecules. For example, a compound capable of antagonising a combination of the 5HT1a and dopamine D4 receptors may provide potential novel approaches for enhancing cognitive function, such as in learning and memory; and for treating diseases of cognitive dysfunction, such as schizophrenia, depression, ALS, anxiety, Parkinson's disease and Alzheimer's disease. It would, therefore, be advantageous to have new polypharmaceutical compounds for the treatment of diseases, and especially neurological disorders.
The present invention addresses one or more of the above-mentioned needs or problems in the art.